N-benzyl-N-alkyl-2,6-dinitro-4-trifluoromethylaniline compounds have been used as herbicides and as plant control regulators. See, for example, U.S. Pat. No. 4,046,809, which defines a class of these compounds that are useful as plant control regulators. These classes of compounds have also found utilities in other areas, for example as germicides.
A method of manufacturing various N-benzyl-N-alkyl-2,6-dinitro-3-amino-4-trifluoromethylaniline compounds is described in U.S. Pat. No. 4,046,809. The U.S. Pat. No. 4,046,809 method of manufacture involves reacting, for example, substantially equimolar quantities of 2,4-dichloro-3,5-dinitrobenzotrifluoride, N-ethyl-2-chloro-6-fluorobenzylamine, and triethylamine. The resulting compound is then reacted with ammonia or lower alkyl-amino or lower di-alkyl-amino compound to give the desired compound.
The U.S. Pat. No. 4,046,809 method of manufacture requires that all reactants be dissolved in a suitable aprotic solvent, such as tetrahydrofuran, a dioxane, or a low molecular weight ether. The solutions were mixed while the temperature was maintained below 10.degree. C., and placed under nitrogen atmosphere for several days. The trialkylamine is a hydrogen acceptor, and any compound which forms an insoluble precipitate, i.e., benzylamine, pyridines, or alkali metal hydroxides, can be used. The precipitated triethylamine hydrochloride is removed, and the solution is mixed with excess ammonia or the appropriate mono- or di-alkyl-amine at a temperature of -15.degree. C. The solvent is then vaporized or otherwise removed. Problems with this method are the reaction time, the need for a solvent system and the need to separate and recover the solvent.
A method of manufacture described in U.S. Pat. No. 4,169,721 involves reacting substantially equimolar quantities of 4-trifluoromethyl -2,5-dinitro-1-chlorobenzene, a substituted benzylamine or a substituted N-alkylbenzylamine, and a trialkylamine or other acid acceptor such as pyridines, alkylpyridines, metal hydroxides or excess benzylamine. Again, this method of manufacture requires that all reactants be dissolved in a suitable aprotic solvent, such as tetrahydrofuran, a dioxane, or a low molecular weight ether. Again, problems with this method are the reaction time, the need for a solvent system and the need to separate and recover the solvent.
The method of manufacture described in U.S. Pat. No. 4,169,721 does not specifically describe a method for preparing the intermediate benzylamine or N-alkylbenzylamine but refers to literature methods involving reductive alkylation of a benzaldehyde and ammonia or an alkylamine. The use of this type of reaction to manufacture the intermediate secondary amine N-ethyl-2-chloro-6-fluoro-benzylamine (EBA) required in the synthesis of flumetralin is shown below: ##STR1##
Problems with this U.S. Pat. No. 4,169,721 method of producing the intermediate amine EBA are the formation of significant quantities of four undesired byproducts due to competing reactions of hydrolysis, dehydrohalogenation and dimerisation. The four undesired byproducts produced when following the synthesis proposed in U.S. Pat. No. 4,169,721 are shown below: ##STR2##
This U.S. Pat. No. 4,169,721 method requires expensive noble metal catalysts and yields significant quantities of undesirable impurities. Gas chromatographic analysis of the reaction mixture obtained by the catalytic reduction of formula II with standard Pt/C catalyst in methanol solvent reveals four separate impurities are present at a combined concentration of approximately 47 weight percent, with a subsequent yield of only 53 weight percent of EBA. Not only would this method require costly separation of the impurities from the desired intermediate, but more importantly, the yield on the expensive starting material is economically unacceptable. The use of sulfided Pt/C catalysts, while reducing the number and quantity of dehalogenated impurities, still resulted in only 63 weight percent EBA, with the remainder being essentially the high molecular weight dimeric impurity shown above.
Great Britain Patent 2,128,603 describes a method of synthesis of N-(dihalobenzyl)-N-alkyl-2,6-dinitro-4-trifluoromethylanilines, and in particular the herbicide flumetralin, via NaBH.sub.4 reduction of a Schiff base. The NaBH4 reagent is prohibitively expensive to effect the desired reduction and requires the addition to the process of yet another solvent such as methanol. This method also results in formation of a benzyl alcohol impurity. This process is similar to the reductive alkylation mentioned in U.S. Pat. No. 4,169,721 except it describes reduction of the intermediate imine (Schiff base), structure II above, with NaBH.sub.4.
GB 2,128,603 also makes reference to prior art synthesis of EBA involving the catalytic (Pt/C) reductive alkylation of an aldehyde.
The GB 2,128,603 route to the secondary amine EBA is shown below: ##STR3##
Manufacturing the herbicidal compounds such as flumetralin is a two step process that begins with the synthesis of the intermediate secondary amine. The various proposed methods described above involve producing an intermediate N-alkyl-2-halo-6-halo-benzylamine that in one embodiment contains a --NH--R moiety in the number 1 position. This intermediate compound is then reacted with 4-chloro-3,5-dinitro-benzotrifluoride (DNCB) or similar compound to form the desired herbicidal compounds, liberating a hydrochloric acid molecule.
U.S. Pat. No. 4,169,721 describes the use of triethylamine in tetrahydrofuran to react with the hydrogen chloride formed during the reaction. This introduces another component with safety and environmental concerns and as described would require purification, for example by filtration of the solid ammonium salt and tetrahydrofuran solvent evaporation. The process of GB 2,128,603 is similar in that it uses toluene as the solvent, and an alkali salt as the acid acceptor. The processes of the a) U.S. Pat. No. 4,169,721 and b) GB 2,128,603 are shown below: ##STR4##
What is needed is a method of manufacturing N-benzyl-N-alkyl-2,6-dinitro-4-trifluoromethylanilines that uses less solvent and less costly reagents, and that has higher yield and less troublesome byproducts.